Nearly twenty percent of the world's cancer burden can be attributed to chronic infectious diseases. Most infection-associated cancers have been shown to have a viral etiology, though bacteria and parasites also contribute to the global cancer burden. All known virus-associated cancers are specifically increased among immunosuppressed individuals, and there are other cancers that likely have a viral etiology because they too are increased following immunosuppression. Lymphoma, anogenital malignancies and lung cancer have been found to be increasingly common in a diverse set of immunosuppressed individuals. We propose to identify a viral etiology of those cancers most likely attributable to infection in this application. Specifically, we will focus on the subset of lymphomas that are more common in immunosuppressed individuals but have not been consistently related to Epstein Barr Virus (Hodgkin lymphoma and diffuse large B-cell lymphoma), the nearly 50% of penile and vulvar cancers that have not been attributed to infection with human papillomavirus (HPV), and a wide variety of lung cancers in a young immunosuppressed population with limited exposure to tobacco. Our overall strategy will be to obtain samples from cancers that are significantly increased in multiple immunosuppressed populations, to perform high throughput sequencing of tumor transcriptomes and computational analyses to identify viral sequences, to develop assays to determine whether the viruses are generally associated with cancers using well documented case-control series, and to begin to investigate the mechanisms of viral carcinogenesis using Merkel Cell polyomavirus (MCPyV) as an example. We bring together a team of investigators with complementary expertise in cancer biology, infectious diseases, virus discovery, computational biology and epidemiology, which will have access to unique tumor specimens originating from individuals with HIV infection in Uganda as well as validation in HIV-negative Ugandans and transplant cohorts from the United States. PUBLIC HEALTH RELEVANCE: There has been tremendous progress in preventing or treating cancers that we know have an infectious etiology, such as developing HBV and HPV vaccines to prevent liver and anogenital cancers respectively, and treating a variety of lymphomas with antivirals. It is likely that other cancers have an infectious etiology and identifying new associations would have a significant impact on early diagnosis, treatment, and prevention of cancer.